Studies on the pathogenesis and the treatment of GM1-gangliosidosis mice

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GM1-gangliosidosis is a progressive neurological disease caused by a deficiency of lysosomal β-galactosidase(β-Gal) and is classified into three clinical forms : infantile, juvenile and adult. We recently generated β-Gal knockout(KO) mice as an authentic model of GM1-gangliosidosis. In this study, we conducted biochemical analysis of the model mice and demonstrated that the accumulation of gangliosides GM1 and asialoGM1 occurred as early as 1-2 weeks of age in their brains. We also generated the C57BL/6 congenic strain of KO mice and revealed the some differences in. storage materials between original crossbred and congenic strains. To evaluate the gene therapy using adeno-associated virus(AAV) vector for GM1-gangliosisosis mice, we injected AAV containing human β-Gal into the mouse brain and demonstrated the enzyme activities were detected only in a limited area for one month. We introduced the wild-type human β-Gal transgene into β-Gal KO mice in order to rescue their GM1-gangliosidosis phenotypes. We also introduced into β-Gal KO mice the mutant human β-Gal transgenes with R201C and I51T amino acid substitutions, which were common for juvenile and adult GM1-gangliosidoses, respectively. Three types of transgenes containing the β-actin promoter/human β-Gal cDNA (wild-type, R201C or I51T) were used. Transgenics were bred with β-Gal KO mice, and the resulting three types of KO/transgenic mice lacked mouse β-Gal gene but had human β-Gal (wild-type, R201C or I51T) transgene. As expected, the wild-type human β-Gal transgene could rescue the mouse GM1-gangliosidosis. KO/transgenic mice expressing mutant human β-Gals might be useful for the studies of pathogenesis and treatment of GM1-gangliosidosis with residual enzyme activities.